ABSTRACT Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. The primary cause of death in patients with breast cancer is the development of metastasis, a process that is still poorly understood. Characterizing genes that regulate the growth and metastatic ability of breast cancer may identify novel biomarkers to help clinicians guide current treatments, and may offer new targets for therapy. We have identified CCN6 [WISP3 (Wnt-1 induced signaling protein 3)] as being down-regulated in tissue samples of breast cancers with high metastatic ability. CCN6 is a member of the CCN family, which mediate cross-talk between the epithelium and the stroma and regulate fundamental processes including cellular differentiation and growth. Emerging data show that CCN proteins are deregulated in cancer. In studies funded by my K08 award, we have begun to study the role of CCN6 in breast cancer, which was unknown. We showed that CCN6 has tumor inhibitory functions in breast cancer in vivo and in vitro. We discovered that CCN6 interferes with the growth effects of IGF-1 and its signaling pathway in the mammary epithelium. Recently, our laboratory made the novel observation that inhibition of CCN6 in benign breast epithelial cells causes an epithelial to mesenchymal transition (EMT) with marked down regulation of E-cadherin. Our central hypothesis is that CCN6 plays a causal role in the pathogenesis of breast cancer. We postulate that loss of CCN6 in the breast promotes tumor growth, invasion and metastasis by (a) regulating the growth effects of IGF-1 on the mammary epithelium, and (b) repressing the E-cadherin complex. CCN6 loss in breast cancer may drive a group of aggressive and metastatic tumors. The specific aims of this project are as follows: Aim 1: To determine the role of CCN6 in regulating the growth of breast cancer in vitro and in vivo and its relationship with IGF-1 signaling pathways; Aim 2: To investigate the biologic implications and the molecular basis of CCN6 mediated epithelial to mesenchymal transition in breast cancer; Aim 3: To determine whether CCN6 loss accelerates the growth of mammary tumors and their metastatic potential using well-characterized mouse models of breast tumorigenesis. We will investigate the effect of CCN6 inhibition on the process of EMT and on IGF-1 signaling in vivo using unique human tissue resources consisting of samples of normal breast, ductal carcinoma in situ (DCIS), invasive carcinomas, and nodal and distant metastases. Regulating the expression of CCN6 may represent an important drug target for prevention and cure of breast cancer. These studies have the potential of providing better diagnosis, more accurate predicting of poor prognosis and open the potential for new therapies. PROJECT NARRATIVE Breast cancer is the second leading cause of cancer deaths in women and is the most common cancer among women. This study addresses an important aspect of women's health, that of how CCN6 regulates the growth and epithelial differentiation of breast tumors and prevents malignant conversion. If we could prevent the loss of CCN6 or reactivate it in metastasizing tumors we would greatly improve breast cancer outcome and save the lives of millions of women. These studies may form the basis of intervention and therapy in breast cancer, potentially preventing premalignant lesions from becoming malignant and metastasizing.